220592-68-7Relevant academic research and scientific papers
Discovery of a luoro-2′-β- C -methyluridine Nucleotide Prodrug (PSI-7977) for the treatment of hepatitis C virus
Sofia, Michael J.,Bao, Donghui,Chang, Wonsuk,Du, Jinfa,Nagarathnam, Dhanapalan,Rachakonda, Suguna,Reddy, P. Ganapati,Ross, Bruce S.,Wang, Peiyuan,Zhang, Hai-Ren,Bansal, Shalini,Espiritu, Christine,Keilman, Meg,Lam, Angela M.,Steuer, Holly M. Micolochick,Niu, Congrong,Otto, Michael J.,Furman, Phillip A.
, p. 7202 - 7218 (2010)
Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5′-phosphate derivative of the β-d-2′-deoxy-2′-α- fluoro-2′-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.
